Phase 3 Clinical Trial_Safety and Efficacy of Ibalizumab for MDR HIV_BB-IND #9776 Project Summary/Abstract [Ibalizumab was designated an Orphan Drug in October, 2014, to treat patients with multidrug resistant HIV. Ibalizumab received Breakthrough Therapy Designation in March, 2015. The FDA has indicated that a single Phase 3 trial demonstrating the efficacy and safety of newly manufactured ibalizumab will satisfy the clinical requirements for a Biological Licensing Application (BLA) for intravenous ibalizumab (see FDA Type C Meeting Minutes, Appended). The research is TMB-301, a Phase 3 clinical trial designed to demonstrate the antiviral activity of ibalizumab after one week of monotherapy at Day 14 and also at Week 25/EOS and the safety of ibalizumab when administered to patients with multi-drug resistant HIV by intravenous (IV) infusion for 24 weeks in combination with an optimized background regimen consisting of other antiretroviral drugs. The results of TMB-301 are expected to show that ibalizumab-based combination therapy using newly manufactured ibalizumab can effectively suppress viral replication in patients infected with multi-drug resistant HIV. The study is expected to confirm that infrequently administered medications such as ibalizumab can provide significant antiviral activity and perhaps demonstrate greater convenience to patients. The research is expected to result directly in the submission of a BLA to the FDA in 2016 for the registration of ibalizumab for the treatment of patients infected with multi-drug resistant HIV.] Ibalizumab is a humanized monoclonal antibody that blocks HIV-1 infection by binding specifically to domain 2 of human CD4, the primary receptor for HIV (Burkly, 1992). Ibalizumab has potent activity against a broad range of HIV strains including multi-drug-resistant HIV, but it does not interfere with CD4-mediated immune functions (Reimann, 1993; Boon, 2002). Over 230 patients have received ibalizumab treatment in FDA- sanctioned, Phase 1 and Phase 2 clinical trials. The results demonstrated that ibalizumab 1) reduces HIV viral loads with potency similar to other approved antiretroviral agents, 2) is active against multi-drug-resistant HIV, 3) is tolerable with no additional side-effects (comparable to placebo), 4) has no discernible drug-drug interactions so it can be combined safely with currently marketed antiretroviral agents and concomitant medications, and 5) exhibits activity with dosing intervals up to four weeks in length (Kuritzkes, 2004; Jacobson, 2009; Norris, 2006; Khanlou, 2011). Collectively, the early clinical trials have all met their protocol- defined objectives for the safety and antiviral efficacy of ibalizumab therapy for HIV-1 infections. The specific objectives of this research include 1) producing additional data demonstrating the efficacy of ibalizumab for the treatment of multi-drug resistant HIV, sufficient to meet FDA requirements for registration, 2) producing additional data demonstrating the safety of ibalizumab for the treatment of multi-drug resistant HIV, sufficient to meet FDA requirements for registration, 3) demonstrating that newly formulated ibalizumab is safe and effective when administered by IV infusion.